Process for preparing arylacetylaminothiazoles

ABSTRACT

The present invention relates to new, efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compounds of formula I:  
                 
 
     or a pharmaceutically acceptable salt thereof, wherein:  
     R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 12  and R 13  are each independently hydrogen, alkyl, aryl or heteroaryl;  
     R 3 , R 7 , R 10  and R 11  are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and  
     X is CH or N,  
     which are novel, potent inhibitors of cyclin dependent kinases (cdks). The present invention also concerns a new process for the preparation of formylarylacetates and formylarylacetic acids.

CROSS-REFERENCE TO RELATED U.S. APPLICATIONS

[0001] This application is a divisional application of U.S. applicationSer. No. 10/067,723, filed Feb. 5, 2002, which is a divisional of U.S.application Ser. No. 09/746,059, filed on Dec. 22, 2000, which is acontinuation-in-part application of (1) U.S. application Ser. No.09/616,627, filed on Jul. 26, 2000, and (2) U.S. application Ser. No.09/616,629, filed on Jul. 26, 2000, which are continuation-in-partapplications of U.S. application Ser. No. 09/464,511, filed Dec. 15,1999.

FIELD OF THE INVENTION

[0002] The present invention concerns new processes for the preparationof 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs,inhibitors of cyclin dependent kinases.

BACKGROUND OF THE INVENTION

[0003] The 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compoundsof formula I

[0004] or a pharmaceutically acceptable salt thereof, wherein:

[0005] R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, R¹² and R¹³ are each independentlyhydrogen, alkyl, aryl or heteroaryl;

[0006] R³, R⁷, R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl,heteroaryl, halogen, hydroxy or alkoxy; and

[0007] X is CH or N,

[0008] are novel, potent inhibitors of cyclin dependent kinases (cdks).They are useful in the therapy of proliferative diseases, for example,cancer, inflammation, autoimmune diseases such as arthritis, viraldiseases, fungal diseases, chemotherapy-induced alopecia,neurodegenerative disorders such as Alzheimer's disease andcardiovascular disease. More specifically, the compounds of formula Iare useful in the treatment of a variety of cancers such as bladder,breast, colon, kidney, liver and lung cancers.

[0009] The preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, keyintermediates in the synthesis of5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles of formula I, hasbeen described (K. S. Kim et al., WO 99/24416, May 20, 1999 andcorresponding U.S. Pat. No. 6,040,321).

[0010] 4-Formylphenylacetic acid has been previously prepared from ethylphenylacetate in four steps which provided <15% overall yield (J. W.Baker et al., J. Chem. Soc. 1956, 404).

[0011] The reaction of 4-bromophenylacetic acid or ester with alkylacrylates using palladium catalysts to give4-(2-alkoxycarbonylvinyl)phenylacetic acid or ester has been previouslyreported in the literature (J. W. Tilley et al., J. Med. Chem. 1991, 34,1125; A. Cerri et al., J. Heterocycl. Chem. 1993, 30, 1581). Theoxidation of β-arylacrylates to give aryl aldehydes has also beenreported (G. Cainelli et al., Synthesis, 1989, 47; D. G. Lee et al.,Can. J. Chem. 1972, 50; D. G. Lee et al., Liebigs Ann. Chem. 1993, 503;S. Antus et al., Liebigs Ann. Chem. 1993, 105).

SUMMARY OF THE INVENTION

[0012] This invention concerns new efficient processes for thepreparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles andanalogs. The processes involve new strategy for the preparation offormylarylacetic acids, key intermediates in the synthesis of5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs,inhibitors of cyclin dependent kinases.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention relates to new, more efficient processesfor the preparation of formylarylacetic acids with application to thesynthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles andanalogs, inhibitors of cyclin dependent kinases. The processes involvereaction of haloarylacetic acids or esters II with olefins III to givevinylarylacetic acids or esters IV. Oxidation of IV with an oxidizingreagent gives formylarylacetic acids or esters V. Compared to theprevious process which takes four steps and has yields less than 15%,the process of the invention can obtain the formylacetic acids or estersin only two steps and at substantially higher yields.

[0014] Subsequent coupling of formylarylacetic acids or esters V with5-(2-oxazolylalkylthio)-2-aminothiazoles VI produces amides VII.Reductive amination of the amide VII with amines affords5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazoles I,inhibitors of cyclin dependent kinases.

[0015] Alternatively, compounds of formula I can be prepared by couplingof haloalkylarylacetic acids VIII with5-(2-oxazolylalkylthio)-2-aminothiazoles VI followed by aminolysis ofthe resulting amides IX with amines.

[0016] The above-described reactions are illustrated in the below Scheme1.

[0017] In formulas I-IX of Scheme 1, the following terms apply:

[0018] R, R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, R¹² and R¹³ are each independentlyhydrogen, alkyl, aryl or heteroaryl;

[0019] R³, R⁷, R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl,heteroaryl, halogen, hydroxy or alkoxy;

[0020] W is halogen or sulfonate (RSO₂O-, CF₃SO₂O-, etc.);

[0021] X is CH or N;

[0022] Y is CHO, C(O)R, COOR, CONRR¹, CN, NO₂, SO₂OR or SO₂NRR¹; and

[0023] Z is hydrogen, CHO, C(O)R, COOR, CONRR¹, CN, NO₂, SO₂OR orSO₂NRR¹.

[0024] Listed below are definitions of various terms used to describethe compounds involved in the processes of the present invention. Thesedefinitions apply to the terms as they are used throughout thespecification (unless specifically indicated otherwise) eitherindividually or as part of a larger group. It should be noted that anyheteroatom with unsatisfied valences is assumed to have the hydrogenatom to satisfy the valences.

[0025] The term “alkyl” or “alk” (i.e., derivative forms of alkyl)refers to optionally substituted straight chain, branched or cyclicmonovalent alkane (saturated hydrocarbon) derived radicals containingfrom 1 to 12 carbon atoms. When substituted, alkyl groups may besubstituted with up to four substituent groups at any available point ofattachment. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and thelike. The alkyl can be optionally substituted with one or more halogensor alkyl groups such as, for example, trifluoromethyl,4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.

[0026] The term “aryl” or derivative forms thereof refers to monocyclicor bicyclic aromatic rings, e.g., phenyl, substituted phenyl and thelike, as well as groups which are fused, e.g., napthyl, phenanthrenyland the like, containing from 6 to 30 carbon atoms. An aryl group canthus contain at least one ring having 6 atoms, with up to five suchrings being present, containing up to 22 or 30 atoms therein, dependingupon optionally alternating (resonating) double bonds between carbonatoms or suitable heteroatoms. Examples of aryl groups include, but arenot limited to, phenyl, naphthyl, anthryl, biphenyl and the like.

[0027] The term “halogen” or “halo” refers to chlorine, bromine,fluorine or iodine, with bromine being the preferred halogen. The term“heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms,containing at least one heteroatom, O, S or N, in which a carbon ornitrogen atom is the point of attachment, and in which one or twoadditional carbon atoms is optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, said heteroaryl group beingoptionally substituted as described herein. Exemplary heteroaryl groupsinclude, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl,imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl,pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl,isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, benzofurazanyl, etc. The heteroaryl groups can beoptionally substituted by one or more groups which include, but are notlimited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl,alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino,alkylS(O)m (where m=0, 1 or 2), thiol and the like.

[0028] The term “pharmaceutically acceptable salt” refers to those saltsof the biologically active compounds which do not significantly oradversely affect the pharmaceutical properties of the compounds, suchas, for example, toxicity, efficacy, etc. and include those salts whichare conventionally employed in the pharmaceutical industry. Suitableexamples of salts include, but are not limited to, those formed withinorganic or organic acids such as hydrochloride, hydrobromide, sulfate,phosphate, etc. Also included, particularly for the intermediatecompounds of the invention, are salts which are unsuitable forpharmaceutical utility but which can be employed otherwise, for example,for isolation or purification of free active compounds or theirpharmaceutically acceptable salts.

[0029] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of the compounds employed in the processes of theinvention embraces all possible stereoisomers and their mixtures. Thedefinition further embraces the racemic forms and the isolated opticalisomers having the specified activity. The racemic forms can be resolvedby physical methods such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates by conventional methods suchas, for example, salt formation with an optically active acid followedby crystallization.

[0030] It should be understood that solvates (e.g., hydrates) of thecompounds of formula I and the intermediate compounds are also withinthe scope of the present invention. Methods of solvation are generallyknown in the art. Therefore, the compounds useful in the processes ofthis invention may be in the free or hydrate form.

[0031] As set forth in Scheme 1, the process for the preparation of5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs involvesthe following transformations:

[0032] (a) reacting a haloarylacetate II with an olefin III in thepresence of a palladium catalyst in a suitable solvent or solventmixtures to give a vinyl-substituted arylacetate IV such asvinylarylacetate.

[0033] It should be appreciated that the term “haloarylacetate” forpurposes of the present invention includes both haloarylacetic acids andesters. Additionally, a sulfonate, for example, RSO₂O- (where R isalkyl, aryl or heteroaryl), CF₃SO₂O- and the like, may be substitutedfor the halogen in the arylacetate or arylacetic acid startingcompounds. The preferred haloarylacetates are haloarylacetic acids withbromophenylacetic acids, such as, for example, 4-bromophenylacetic acid,most preferred. The olefin includes alkenes and polymers derived from analkene such as ethyl or methyl acrylate. The palladium catalystsinclude, but are not limited to, palladium acetate or diacetate,palladium halides, etc., with the palladium diacetate preferred. Otherstandard catalysts may be employed although less conveniently. Aconventional ligand for the palladium catalyst such as trialkyl ortriarylphosphine can also be employed. Suitable solvent(s) includesolvents such as hydrocarbons, ethers, amides, for example,dimethylformamide (“DMF”), ketones, etc., or mixtures thereof, withamides such as DMF preferred.

[0034] (b) reacting the vinyl-substituted arylacetate IV, likevinylarylacetate, obtained in step (a) with an oxidizing reagent in asuitable solvent or solvent mixtures to give a formylarylacetate V.

[0035] The oxidizing reagent includes, but is not limited to, O₃, KMnO₄,NaIO₄/OsO₄, etc., with NaIO₄/OsO₄ preferred. Suitable solvent(s) includesolvents such as hydrocarbons, ethers, esters, amides, and the like,mixtures thereof, or aqueous mixtures thereof, with an ether and watermixture preferred.

[0036] For example, the oxidative cleavage of the double bond of formulaIV by a reagent such as osmium tetroxide with sodium periodate in adioxane/water mixture gives the desired vinyl-substituted arylaceticacid or arylacetate, such as formylphenylacetic acid orformylphenylacetate.

[0037] (c) reacting the formylarylacetate V obtained in step (b) with a5-(2-oxazolylalkylthio)-2-aminothiazole compound VI in the presence of acoupling reagent and in a suitable solvent or solvent mixtures to givean amide VII.

[0038] The 5-(2-oxazolylalkylthio)-2-aminothiazoles include5-(5-substituted-2-oxazolyl-alkylthio)-2-aminothiazole compounds with5-(5-t-butyl-2-oxazolylalkylthio)-2-amino-thiazole preferred. Thecoupling reagents include, but are not limited to, carbodiimides,haloformates, thionyl halide and the like, with thionyl halidepreferred. Suitable solvent(s) include aprotic solvents such ashydrocarbons, halogenated hydrocarbons, ethers, esters, etc., withhalogenated hydrocarbons such as dichloromethane preferred.

[0039] (d) reacting the amide VII obtained in step (c) with an amine inthe presence of a reducing reagent in a suitable solvent or solventmixtures to give5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazole I.

[0040] The amine used in reaction (d) includes primary and secondaryamines with primary aliphatic amines preferred. The reducing reagentsinclude, but are not limited to, NaBH₄, NaBH(OAc)₃, Et₃SiH/TFA and thelike with NaBH(OAc)₃ preferred. Suitable solvent(s) includehydrocarbons, halogenated hydrocarbons, ethers, esters, etc., ormixtures thereof, with ethers such as tetrahydrofuran (“THF”) preferred.

[0041] Alternatively, the compounds of formula I can be prepared by:

[0042] (c′) reacting the haloalkylarylacetate VIII with a5-(2-oxazolylalkylthio)-2-aminothiazole compound VI in the presence of acoupling reagent and in a suitable solvent or solvent mixtures to givean amide IX.

[0043] The 5-(2-oxazolylalkylthio)-2-aminothiazoles include5-(5-substituted-2-oxazolyl-alkylthio)-2-aminothiazole compounds with5-(5-t-butyl-2-oxazolylalkylthio)-2-amino-thiazole preferred. Thecoupling reagents include, but are not limited to, carbodiimides,haloformates, thionyl halide and the like, with the former preferred,for example, an alkylcarbodiimide. Suitable solvent(s) include aproticsolvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters,etc., with halogenated hydrocarbons such as dichloromethane preferred.

[0044] For instance, treatment of haloalkylarylacetate orhaloalkylarylacetic acid VIII such as haloalkylphenylacetate orhaloalkylphenylacetic acid with 5-(2-oxazolylalkylthio)-2-aminothiazoleVI provides a haloalkyl-substituted phenylacetamide IX.

[0045] (d′) reacting the amide IX obtained in step (c′) with an amine ina suitable solvent or solvent mixtures to give5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazole I.

[0046] The amine used in reaction (d′) includes primary and secondaryamines with primary aliphatic amines preferred. Suitable solvent(s)include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides,etc., with amides such as DMF preferred.

[0047] For example, the reaction under reductive amination conditionswith a primary or secondary amine in the presence of sodiumcyanoborohydride or hydrogen in the presence of a catalyst gives thecompounds of formula I.

[0048] Alternatively, the aldehydes of formula VII may be reacted withan organometallic reagent such as methylmagnesium bromide in a suitablesolvent or solvent mixture, such as, for example, ether to give analcohol derivative. The alcohol derivative is converted to itscorresponding halide such as a chloride by a chlorinating agent such asthionyl chloride. The halide compound such as the chloride compound maythen be converted to a compound of formula I by reaction with an excessof a primary or secondary amine in a suitable solvent such as ethanol.

[0049] The starting compounds of Scheme I are commercially available ormay be prepared by methods known to one of ordinary skill in the art.

[0050] To further illustrate Scheme 1, a process to makeformylphenylacetic acids with application to the synthesis of5-(5-t-butyl-2-oxazolylmethylthio)-2-[(aminomethyl)phenyl-acetyl]aminothiazolesand analogs thereof, for example, starts with the reaction ofhalophenylacetic acids II such as bromophenylacetic acid (R=R¹=R²=R³=H,X=Br) with alkyl acrylate III such as ethyl acrylate (R⁴=Z=H, Y=CO₂Et)to give (2-ethoxycarbonyl)vinylphenylacetic acids IV (R=R¹=R²=R³=R⁴=Z=H,Y=CO₂Et). Oxidation of IV with a suitable oxidizing reagent givesformylphenylacetic acids V (R=R¹=R²=R³=R⁴=H). Coupling of V with5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole VI (R⁶=R⁷=R⁸=R⁹=R¹⁰=H,R¹¹=t−Bu) produces amides VII (R¹=R²=R³=R⁴=R⁶=R⁷=R⁸=R⁹=R¹⁰=H, R¹¹=t−Bu).Reductive amination of VII with amines affords5-(5-t-butyl-2-oxazolylalkylthio)-2-(aminomethyl)phenylacetylamino-thiazolesI, inhibitors of cyclin dependent kinases. Alternatively, compounds offormula I can be prepared by coupling of haloalkylphenylacetic acidsVIII such as bromomethylphenylacetic acid (R=R¹=R²=R³=R⁴=R⁵=H) with5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole VI followed byaminolysis of the resulting amides IX with amines.

[0051] The following examples demonstrate certain aspects of the presentinvention. However, it is to be understood that these examples are forillustration only and do not purport to be wholly definitive as toconditions and scope of this invention. It should be appreciated thatwhen typical reaction conditions (e.g., temperature, reaction times,etc.) have been given, the conditions both above and below the specifiedranges can also be used, though generally less conveniently. Theexamples are conducted at room temperature (about 23° C. to about 28°C.) and at atmospheric pressure. All parts and percents referred toherein are on a weight basis and all temperatures are expressed indegrees centigrade unless otherwise specified.

[0052] A further understanding of the invention may be obtained from thenon-limiting examples which follow below.

EXAMPLES Example 1

[0053] A. Preparation of 4-[2-(Ethoxycarbonyl)vinyl]phenylacetic Acid

[0054] To a stirred solution of 4-bromophenylacetic acid (43.0 g, 200mmol) in dimethyl formamide (400 mL) in a round bottom flask undernitrogen atmosphere at room temperature was added ethyl acrylate (43.3mL, 400 mmol), palladium diacetate (0.90 g, 4 mmol), triphenylphosphine(2.10 g, 8 mmol), and diisopropylethylamine (87.2 mL, 500 mmol). Thereaction mixture was heated to 100° C. for 43 hours, cooled to roomtemperature, and hydrochloric acid (1N, 1 L) was added. To the reactionmixture was added ethyl acetate (500 mL), the aqueous layer wasextracted with ethyl acetate (2×500 mL), and the combined organic layerswashed with hydrochloric acid (1N, 500 mL), water (500 mL) and saturatedsodium chloride solution (250 mL), then dried over sodium sulfate,filtered and evaporated in vacuo to provide the title compound as amixture of cis and trans isomers (46.9 g, 100%).

example 2

[0055] B. Preparation of 4-Formylphenylacetic Acid

[0056] To a stirred solution of the title compound of Example 1 (46.9 g,200 mmol) in dioxane (500 mL) and water (500 mL) was added osmiumtetroxide (0.5 g, 4% in water), followed by sodium periodate (85.56 g,400 mmol). The reaction mixture was monitored by HPLC, stirred for 1hour and N-methylmorpholine (1.0 g) was added, followed by additionalosmium tetroxide (1.0 g) after another 16 hours. After 4 hours stirringat room temperature, additional sodium periodate (40 g) was added, thereaction stirred for 21 hours, filtered, and the filter cake washed withethyl acetate (500 mL). The phases were separated, the aqueous layerextracted with ethyl acetate (500 mL), the remaining aqueous layeracidified with hydrochloric acid (30 mL), extracted with ethyl acetate(500 mL), and the combined organic phases washed with water (500 mL),saturated sodium chloride solution (250 mL), dried over sodium sulfate,filtered and the solvent removed in vacuo. The wet solid was trituratedwith methyl tert-butyl ether (50 mL) and to the resulting slurry wasadded pentane (100 mL). The slurry was filtered, the solid product waswashed with pentane (2×25 mL) and dried to give the title compound (12.4g, 38%). HPLC: 2.19 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). ¹H NMR (d₆-DMSO): δ 9.99 (s, 1H), 7.85-7.87 (d,2H), 7.49-7.51 (d, 2H); 3.72 (s, 3H).

Example 3

[0057] C. Preparation of5-(5-t-Butyl-2-oxazolylalkylthio)-2-(4-formylphenyl)-acetylaminothiazole

[0058] Oxalyl chloride (2.0 M in CH₂Cl₂, 9.1 mL, 18.2 mmol, 3 eq) wasadded slowly to a solution of the title compound of Example 2 (2.0 g,12.2 mmol, 2 eq) in CH₂Cl₂ at 0° C. The resultant acyl chloridecontaining reaction mixture was added to a solution of2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazoledropwise (1.64 g, 6.09 mmol) and triethylamine (3.2 mL) indichloromethane. The reaction was stirred at 0° C. for 5 minutes andthen allowed to warm to room temperature. After 30 minutes, saturatedaqueous NaHCO₃ was added with CH₂Cl₂ (220 mL), the organic extractwashed with saturated aqueous NaHCO₃, 0.1N HCl, saturated NaCl, anddried over MgSO₄. Concentration in vacuo gave a brown oil which wastriturated with hexane followed by ethyl acetate to provide 1.03 g ofyellowish solid. An additional 1.02 g of material was obtained from thefiltrate by flash chromatography on silica gel eluting with a gradientof 50-60% ethyl acetate in hexane to provide a total of 2.05 g (81%) ofthe title compound. HPLC: 97% at 3.90 min (YMC S5 ODS column 4.6×50 mm,10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid,4 mL/min, monitoring at 220 nm).

Example 4

[0059] D. Preparation of5-(5-t-Butyl-2-oxazolylalkylthio)-2-[4-(3-hydroxy-2,2-dimethylpropylaminomethyl)phenyl]acetylaminothiazole

[0060] To the title compound of Example 3 (1.1 g, 2.65 mmol, 1 eq)dissolved in 20 mL of tetrahydrofuran and cooled to 0° C. was added3-amino-2,2-dimethyl-1-propanol (1.0 g, 9.7 mmol, 3.7 eq), followed byacetic acid (1 mL) and sodium triacetoxyborohydride (2.6 g, 12.3 mmol,4.6 eq). The reaction was stirred at room temperature for 1 hour.Aqueous NaHCO₃ was added, and the mixture was extracted with ethylacetate. The organic extracts were washed with water, dried over MgSO₄,and concentrated in vacuo. The material was acidified by addition of 4NHCl in dioxane to a solution in methanol. The product was also purifiedby flash chromatography on silica gel eluting with 10% methanol in ethylacetate with 2.7% triethylamine to provide 530 mg (40%) of the titlecompound as a beige solid. HPLC: 97% at 3.28 min (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 5

[0061] C′ Preparation of5-(5-t-Butyl-2-oxazolylalkylthio)-2-(4-bromo-methylphenyl)acetylaminothiazole

[0062] 1,3-Dicyclohexylcarbodiimide (7.18 g, 34.8 mmol, 1.25 eq) wasadded to a mixture of 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole(7.5 g, 27.8 mmol, 1 eq) and 4-bromomethylphenylacetic acid (7.97 g,34.8 mmol, 1.25 eq) in 175 mL of CH₂Cl₂ at 0° C. The reaction mixturewas allowed to warm to room temperature. After 30 minutes LC/MSindicated that the reaction was complete, the mixture was filtered andconcentrated in vacuo onto 20 g of silica gel. The material was purifiedby flash chromatography on silica gel eluting with 60% ethyl acetate inhexane to provide 11.5 g (83%) of the title compound as a yellow solid.

[0063] In an alternative method of preparation,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72mmol, 2 eq) was added to a mixture of5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole (2.0 g, 7.42 mmol, 1eq) and 4-bromomethyl phenylacetic acid (2.60 g, 11.3 mmol, 1.5 eq) inCH₂Cl₂ (30 mL) under N₂ at room temperature. After 1 hour, the reactionwas diluted with 20 mL of ethyl acetate and washed with saturatedaqueous NaHCO₃ (2×20 mL). The organic phase was then washed with 10%aqueous citric acid, dried over MgSO₄, and concentrated in vacuo toprovide a yellow solid. This material was triturated with ether toprovide 3.01 g (84.4%) of the title compound. HPLC: R.T.=3.693 min (YMCS5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); ¹H NMR(CDCl₃):δ 7.37-7.24 (m, 5H), 6.54 (s, 1H), 4.47 (s, 2H), 3.93 (s, 2H),3.79 (s, 2H), 1.27 (s, 9H).

Example 6

[0064] D′ Preparation of5-(5-t-Butyl-2-oxazolylalkylthio)-2-[4-(aminomethyl)phenyl]-acetylaminothiazole

[0065] The title compound of Example 5 (70% pure, 1.05 g, 1.53 mmol, 1eq) was dissolved in 40 mL of N,N-dimethylformamide and cooled to −70°C. Excess liquid ammonia (6 mL) was added, and after sealing thereaction vessel, the mixture was allowed to warm to room temperature.After 1 hour, the reaction was diluted with ethyl acetate, washed withwater (20 mL) and saturated aqueous NaCl, dried over MgSO₄, andconcentrated in vacuo. The resulting yellow oil was purified bypreparative HPLC to provide 270 mg (42.4%) of the title compound. HPLCR.T.=3.17 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220nm).

[0066] In the foregoing, there has been provided a detailed descriptionof particular embodiments of the present invention for the purpose ofillustration and not limitation. It is to be understood that all othermodifications, ramifications and equivalents obvious to those havingskill in the art based on this disclosure are intended to be includedwithin the scope of the invention as claimed.

What is claimed is:
 1. A process for the preparation of a compoundhaving the formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R⁴, R⁵,R⁶, R⁸, R⁹, R¹² and R¹³ are each independently hydrogen, alkyl, aryl orheteroaryl; R³, R⁷, R¹⁰ and R¹¹ are each independently hydrogen, alkyl,aryl, heteroaryl, halogen, hydroxy or alkoxy; and X is CH or N; whichcomprises the steps of: (a) reacting an arylacetate or an arylaceticacid having the formula II

10 wherein: R¹, R², R³ and X are as described hereinabove; R ishydrogen, alkyl, aryl or heteroaryl; and W is halogen or sulfonate; withan olefin having the formula III

10 wherein: Y is CHO, C(O)R, COOR, CONRR¹, CN, NO₂, SO₂OR or SO₂NRR¹; Zis hydrogen, CHO, C(O)R, COOR, CONRR¹, CN, NO₂, SO₂OR or SO₂NRR¹; and R,R¹ and R⁴ are as described hereinabove; in the presence of a palladiumcatalyst in a suitable solvent or solvent mixture to form avinyl-substituted arylacetate or vinyl-substituted arylacetic acid; (b)reacting the vinyl-substituted arylacetate or vinyl-substitutedarylacetic acid with an oxidizing reagent in a suitable solvent orsolvent mixture to form a formylarylacetate or formylarylacetic acidcompound; (c) reacting the formylarylacetate or formylarylacetic acidcompound with a 5-(oxazolylalkylthio)-2-aminothiazole compound havingthe formula VI

10 wherein: R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as described hereinabove; inthe presence of a coupling reagent in a suitable solvent or solventmixture to form an amide; and (d) reacting the amide with an amine inthe presence of a reducing reagent in a suitable solvent or solventmixture to form the compound of formula I.
 2. The process as recited inclaim 1, wherein the arylacetate or the arylacetic acid in step (a) is ahaloarylacetate or a haloarylacetic acid.
 3. The process as recited inclaim 2, wherein the haloarylacetic acid is a bromoarylacetic acid. 4.The process as recited in claim 3, wherein the bromoarylacetic acid is4-bromophenylacetic acid.
 5. The process as recited in claim 1, whereinthe olefin in step (a) is an alkyl acrylate.
 6. The process as recitedin claim 1, wherein the palladium catalyst in step (a) is palladiumacetate, palladium diacetate or palladium halide.
 7. The process asrecited in claim 6, wherein the palladium catalyst is palladiumdiacetate.
 8. The process as recited in claim 1, wherein the solvent instep (a) is a hydrocarbon, an ether, an amide, a ketone or a mixturethereof.
 9. The process as recited in claim 8, wherein the solvent isthe amide and the amide is dimethylformamide.
 10. The process as recitedin claim 1, wherein step (a) forms a vinylarylacetate or avinylarylacetic acid.
 11. The process as recited in claim 1, wherein theoxidizing reagent in step (b) is O₃, KMnO₄ or NaIO₄/OsO₄.
 12. Theprocess as recited in claim 11, wherein the oxidizing reagent isNaIO₄/OsO₄.
 13. The process as recited in claim 1, wherein the solventin step (b) is a hydrocarbon, an ether, an ester, an amide, a mixturethereof or an aqueous mixture thereof.
 14. The process as recited inclaim 13, wherein the solvent is the aqueous mixture of an ether andwater.
 15. The process as recited in claim 1, wherein the5-(2-oxazolylalkylthio)-2-aminothiazole compound in step (c) is a5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound.
 16. Theprocess as recited in claim 15, wherein the5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound is5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole.
 17. The process asrecited in claim 1, wherein the coupling reagent in step (c) is acarbodiimide, a haloformate or a thionyl halide.
 18. The process asrecited in claim 17, wherein the coupling reagent is the thionyl halide.19. The process as recited in claim 1, wherein the solvent in step (c)is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester or amixture thereof.
 20. The process as recited in claim 19, wherein thesolvent is the halogenated hydrocarbon and the halogenated hydrocarbonis dichloromethane.
 21. The process as recited in claim 1, wherein theamine in step (d) is a primary amine or a secondary amine.
 22. Theprocess as recited in claim 21, wherein the amine is the primary amineand the primary amine is a primary aliphatic amine.
 23. The process asrecited in claim 1, wherein the reducing reagent in step (d) is NaBH₄,NaBH(OAc)₃ or Et₃SiH/TFA.
 24. The process as recited in claim 23,wherein the reducing reagent is NaBH(OAc)₃.
 25. The process as recitedin claim 1, wherein the solvent in step (d) is a hydrocarbon, ahalogenated hydrocarbon, an ether, an ester or a mixture thereof. 26.The process as recited in claim 25, wherein the solvent is the ether andthe ether is tetrahydrofuran.
 27. A process for the preparation of acompound having the formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R⁴, R⁵,R⁶, R⁸, R⁹, R¹² and R¹³ are each independently hydrogen, alkyl, aryl orheteroaryl; R³, R⁷, R¹⁰ and R¹¹ are each independently hydrogen, alkyl,aryl, heteroaryl, halogen, hydroxy or alkoxy; and X is CH or N; whichcomprises the steps of: (a) reacting an alkylarylacetate oralkylarylacetic acid compound having the formula VIII

10 wherein: R¹, R², R³, R⁴, R⁵ and X are as described hereinabove; R ishydrogen, alkyl, aryl or heteroaryl; and W is halogen or sulfonate; witha 5-(2-oxazolylalkylthio)-2-aminothiazole compound having the formula VI

10 wherein: R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as described hereinabove; inthe presence of a coupling reagent and in a suitable solvent or solventmixture to form an amide; and (b) reacting the amide with an amine in asuitable solvent or solvent mixture to form the compound of formula I.28. The process as recited in claim 27, wherein the alkylarylacetate oralkylarylacetic acid in step (a) is a haloalkylarylacetate or ahaloalkylarylacetic acid.
 29. The process as recited in claim 28,wherein the haloalkylarylacetic acid is a bromoalkylarylacetic acid. 30.The process as recited in claim 29, wherein the bromoalkylarylaceticacid is bromomethylphenylacetic acid.
 31. The process as recited inclaim 27, wherein the 5-(2-oxazolylalkylthio)-2-aminothiazole compoundin step (a) is a 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazolecompound.
 32. The process as recited in claim 31, wherein the5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound is5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole.
 33. The process asrecited in claim 27, wherein the coupling reagent in step (b) is acarbodiimide, a haloformate or a thionyl halide.
 34. The process asrecited in claim 33, wherein the coupling reagent is the carbodiimideand the carbodiimide is an alkylcarbodiimide.
 35. The process as recitedin claim 27, wherein the solvent is a hydrocarbon, a halogenatedhydrocarbon, an ether, an ester or a mixture thereof.
 36. The process asrecited in claim 35, wherein the solvent is the halogenated hydrocarbonand the halogenated hydrocarbon is dichloromethane.
 37. The process asrecited in claim 27, wherein the amine in step (b) is a primary amine ora secondary amine.
 38. The process as recited in claim 37, wherein theamine is the primary amine and the primary amine is a primary aliphaticamine.
 39. The process as recited in claim 27, wherein the solvent instep (b) is a hydrocarbon, a halogenated hydrocarbon, an ether, anester, an amide or a mixture thereof.
 40. The process as recited inclaim 39, wherein the solvent is an amide and the amide isdimethylformamide.
 41. A process for the preparation of a compoundhaving the formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R⁴, R⁵,R⁶, R⁸, R⁹, R¹² and R¹³ are each independently hydrogen, alkyl, aryl orheteroaryl; R³, R⁷, R¹⁰ and R¹¹ are each independently hydrogen, alkyl,aryl, heteroaryl, halogen, hydroxy or alkoxy; and X is CH or N; whichcomprises the steps of: (a) reacting an aldehyde having the formula VII

10 wherein: R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and X are asdescribed hereinabove; with an organometallic reagent in a suitablesolvent or solvent mixture to form an alcohol derivative; (b) reactingthe alcohol derivative with a halide; and (c) reacting the halidecompound with an excess of a primary amine or a secondary amine in asuitable solvent, or solvent mixture to form the compound of formula I.42. The process as recited in claim 41, wherein the organometallicreagent in step (a) is methylmagnesium bromide.
 43. The process asrecited in claim 41, wherein the solvent in step (a) is ether.
 44. Theprocess as recited in claim 41, wherein the halide in step (b) isthionyl chloride.
 45. The process as recited in claim 41, wherein thesolvent in step (c) is ethanol.
 46. A process for the preparation of aformylarylacetate or formylarylacetic acid which comprises the followingsteps: (a) reacting a haloarylacetate or haloarylacetic acid havingformula II

10 wherein: R is hydrogen, alkyl, aryl or heteroaryl; R¹ and R² are eachindependently hydrogen, alkyl, aryl or heteroaryl; R³ is hydrogen,alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; W is halogen orsulfonate; and X is CH or N; with an olefin having the formula III

10 wherein: R⁴ is hydrogen, alkyl, aryl or heteroaryl; Y is CHO, C(O)R,COOR, CONRR¹, CN, NO₂, SO₂OR or SO₂NRR¹; Z is hydrogen, CHO, C(O)R,COOR, CONRR¹, CN, NO₂, SO₂OR or SO₂NRR¹; and R and R¹ are as describedhereinabove; in the presence of a palladium catalyst in a suitablesolvent or solvent mixture to form a vinyl-substituted arylacetate orvinyl-substituted arylacetic acid; and (b) reacting thevinyl-substituted arylacetate or vinyl-substituted arylacetic acid withan oxidizing reagent in a suitable solvent or solvent mixture to formthe formylarylacetate or formylarylacetic acid compound.
 47. The processas recited in claim 46, wherein the olefin in step (a) is alkylacrylate.
 48. The process as recited in claim 47, wherein the alkylacrylate is ethyl acrylate.
 49. The process as recited in claim 46,wherein the oxidizing reagent in step (b) is O₃, KMnO₄ or NaIO₄/OsO₄.50. The process as recited in claim 49, wherein the oxidizing reagent isNaIO₄/OsO₄.